The placenta can be a site for specific toxic action compromising the growth and survival of the conceptus, e.g., cadmium can produce placental necrosis and fetal death in rats. During the past three years, studies were undertaken to determine if the human placenta can be selectively affected by environmental agents at levels detected in animals or humans. An in vitro dual perfused, recirculating human placental preparation was developed to study the normal physiology and toxic response to cadmium without mother or baby being involved. The human placental perfusion system can maintain the placenta morphologically (ultrastructurally), physiologically and biochemically for periods in excess of 12 hours. When Cd is introduced into the maternal perfusate at such (Cd) noted in rat plasma for a placental toxic dose, there is a rapid accumulation of cd in the placental with little passage to the fetal circuit. Within twelve hours following the administration of Cd, there is a dose related (10, 20, or 100nmoles/ml initial dose) increase in necrosis, subsynctiotrophoblastic vesiculation, stromal edema, fetal volume loss (leakiness), (within 12 hours) and decrease in human chorionic gonadotropin synthesis and release (within 4 hours). The objectives of this proposal are four-fold: 1. to establish an in vitro human placental perfusion model for periods of 24-36 hours for determining the toxic interactions and distribution of environmental agents at circulating blood levels noted in animals and humans, and for comparing this in vitro model with other animal and human studies. The proposed studies would involve understanding the normal physiological functioning of the placenta (hormone secretion, transport processes, especially receptor-mediated endocytosis for vitamin magnetic induction12 and other nutrients, and energy metabolism); 2. to determine the mechanisms by which acute exposure to cadmium produces placental toxicity in the human and rodent and whether protection can be provided by other metals (Zn, Se) and under other conditions (induction of metallothionein); 3. to compare the acute effects of Cd and to find a no effect dose in placentae from normal mothers and from smoking mothers in relationship to metallothionein content and induction, toxic response, and potential protection of chronic low Cd exposure to acute Cd exposure and 4. to utilize this in vitro human placental perfusion model to investigate the potential for other suspected placental toxins in animals, e.g., Pb and chloroform, to be directly placental toxic in the human under well-controlled conditions.